Misuse preventative, controlled release formulation

ABSTRACT

Disclosed is a misuse preventative, controlled release composition in the form of a multilayered oral dosage form. A first layer contains a plurality of controlled release microparticles having a pharmaceutically active agent (for example, an opioid analgesic) disposed therein. A second layer comprises a pharmaceutically active agent that can be the same or different from the pharmaceutically active agent in the microparticles. The composition further comprises a superabsorbent material disposed within the first layer, the second layer, or both the first layer and the second layer. When crushed, either intentionally or accidentally, and exposed to an aqueous medium, the superabsorbent material swells to encapsulate the microparticles, which remain substantially intact thereby retarding the release of the pharmaceutically active agent from the composition.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/195,833, filed Mar. 3, 2014, which is a continuation of U.S. patentapplication Ser. No. 13/919,499, filed Jun. 17, 2013, now U.S. Pat. No.8,685,447, which is a continuation of U.S. patent application Ser. No.12/639,664, filed Dec. 16, 2009, now U.S. Pat. No. 8,486,449, whichclaims the benefit of and priority to U.S. Provisional PatentApplication Ser. No. 61/138,092, filed Dec. 16, 2008, the entirecontents of each of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates generally to a controlled releaseformulation for the delivery of at least one pharmaceutically activeagent, and more specifically, the invention relates to a misusepreventative, controlled release formulation, which maintains itscontrolled release properties for at least one pharmaceutically activeagent even when bisected or crushed, and exposed to various media.

BACKGROUND OF THE INVENTION

Although significant developments have been made in the field of drugdelivery, concerns remain for drugs (for example, opioid analgesics)that are subject to abuse. Furthermore, the number of legitimatepatients misusing such drugs, either deliberately or accidentally,represents a serious medical problem. In particular, patient risk can beheightened when controlled release formulations are used because largeramounts of the pharmaceutically active agent are typically incorporatedinto these formulations to facilitate reduced dosing frequency. However,while controlled release formulations offer greater convenience andoften an improved adverse event profile, serious problems can occur ifthe control release mechanism is compromised in any way, for example, byaccidental chewing or grinding of, or other damage to the tablet, orco-ingestion with alcohol. Under these scenarios, immediate release ofthe pharmaceutically active agent followed by the rapid absorption of upto a total daily dose of the pharmaceutical agent can have potentiallyfatal consequences.

While a number of approaches have been tried to address the abuse andmisuse of certain drugs, including, for example, the use of deterrentformulations, agonist/antagonist formulations, and prodrug formulations,the commercialization of these approaches has been limited to date.

Deterrent formulations are formulations that contain a noxioussubstance, such as, capsaicin, an emetic, or niacin. The objective is toprevent deliberate abuse by inflicting a painful or otherwise unpleasantreaction should the formulation be crushed or otherwise damaged prior toingestion. For example, U.S. Patent Publication Nos. 2003/0068370,2003/0068392, and 2007/0020188 describe incorporation of aversive agents(e.g., a bitter agent, an irritant, or an emetic agent) into a dosagecontaining an opioid analgesic. The aversive agents discourage an abuserfrom tampering with the dosage form and thereafter inhaling or injectingthe tampered dosage. The potential risk of such additives to thelegitimate user who accidentally damages the tablet is not addressed bysuch formulations.

Antagonist formulations contain inhibitors (antagonists) of thetherapeutic drug. When the formulation is crushed, the inhibitors areintended to prohibit or reverse the action of the pharmaceuticallyactive agent, thereby reducing or eliminating any benefit fornon-medical use. For example, naloxone is combined with pentazocine(Talwin®, sold by Sanofi-Winthrop) to deter parenteral abuse ofpentazocine. Naloxone is intended to block the binding of pentazocine toopioid receptors. Similarly, naloxone has been added to abuprenorphine-containing formulation (Temgesic®, sold by Reckitt &Colman). In addition, naltrexone, an opioid receptor antagonist, hasbeen added to a morphine-containing formulation (Embeda®, sold by KingPharmaceuticals, Inc.). It is understood, however, that this approach,can expose legitimate patients to unnecessary drugs, and can potentiallyinhibit effective therapy because the inhibitors may be released duringnormal passage through the gastrointestinal tract. These formulationsalso assume that effective inhibition can be achieved (i.e., that thebioavailability, pharmacokinetics and relative affinities of the agonistand antagonist can be matched so as to elicit effective inhibition inthe intended recipient). U.S. Pat. Nos. 3,773,955 and 3,966,940, forexample, describe formulations containing combinations of opioidagonists and antagonists, in which the antagonist does not block thetherapeutic effect when the mixture is administered orally but blocksanalgesia, euphoria or physical dependence when administeredparenterally in crushed form by an abuser.

Prodrug formulations rely on in vivo metabolic conversion of the prodruginto the active drug by enzymes found, for example, in thegastrointestinal tract. While these formulations may prevent euphoriavia intravenous or nasal administration of the drug, they do not addressthe problems associated with potential intoxication (for example,alcohol intoxication) post oral administration.

Because of such limitations with existing technologies, there exists anongoing need for misuse preventative, controlled release formulationsthat can reduce the risk of intentional abuse and accidental misuse offormulations containing a pharmaceutically active agent.

SUMMARY OF THE INVENTION

The invention is based, in part, upon the discovery that it is possibleto create a drug delivery platform where the compositions are oraldosage forms that permit the controlled release of at least onepharmaceutically active agent disposed within the formulation even afterbeing sectioned (for example, bisected) or crushed. The platform isparticularly useful for the administration of pharmaceutically activeagents that are capable of misuse (either deliberate or accidental butin either case causing harm), abuse and/or that have a narrowtherapeutic index. Agents capable of harmful misuse or abuse, include,for example, analgesics (for example, opioid analgesics), hypnoticagents, anxiolytic agents, central nervous system (CNS), and respiratorystimulating agents. Examples of narrow therapeutic index drugs includetheophylline, lithium carbonate, and digoxin.

In one aspect, the invention provides a solid composition (oral dosageform) for the oral administration of at least one pharmaceuticallyactive agent. The composition comprises (a) a first layer comprising afirst population of controlled release microparticles having at leastone pharmaceutically active agent disposed therein; (b) a second layercomprising a pharmaceutically active agent disposed therein; and (c) asuperabsorbent material disposed within the first layer, the secondlayer, or both the first layer and the second layer. In another aspect,the invention provides a solid composition (oral dosage form) for theoral administration of at least one pharmaceutically active agent. Thecomposition comprises (a) a first layer comprising a superabsorbentmaterial and a first population of controlled release microparticleshaving at least one pharmaceutically active agent disposed therein; and(b) a second layer comprising a pharmaceutically active agent disposedtherein.

In each of the foregoing aspects, when the composition is exposed intactto an aqueous environment, the pharmaceutically active agent disposed inthe second layer is initially released at a faster rate than thepharmaceutically active agent disposed in the first layer. At least onepharmaceutically active agent is released from the intact formulationover a prolonged period of time (for example, for at least 6 hours, atleast 8 hours, at least 12 hours, at least 18 hours, or at least 24hours). In certain embodiments, at least 50%, preferably 60%, morepreferably 70%, and even more preferably 80% of at least onepharmaceutically active agent is prevented from being releasedsubstantially immediately (for example, within 30 minutes) from theintact formulation.

In addition, when the composition is crushed and exposed to an aqueousenvironment, the superabsorbent material swells to create a hard, rigidgel that traps the microparticles, which remain substantially intact. Asa result, and in addition to the controlled release properties providedby the microparticles themselves, the hard gel depending upon itscomposition, may provide controlled release of at least onepharmaceutically active agent disposed therein. Depending upon the modeof abuse, the compositions of the invention create an unpleasantexperience for the abuser, make it difficult to extract thepharmaceutically active agent, and/or prevent dose dumping. For example,when crushed and snorted up a nostril, the superabsorbent materialproduces a hard gel that creates an unpleasant experience. Furthermore,if crushed and exposed to an extraction media, the superabsorbantmaterial can absorb all of the extraction media. The resulting gel canbe difficult to push through the needle of a syringe. Furthermore, whencrushed and administered, the microparticles, or a combination of themicroparticles and the gel, maintain controlled release of thepharmaceutically active agent and reduce or eliminate the potential fordose dumping. In certain embodiments, at least 50%, preferably 60%, morepreferably 70%, and even more preferably 80% of at least onepharmaceutically active agent is prevented from being releasedsubstantially immediately (for example, within 30 minutes) from theformulation. As a result, the compositions of the invention prevent dosedumping in water, alcohol (for example, ethanol), and other media ofvarious pH even if the formulations have been broken or crushed.

The pharmaceutically active agent present in the first layer and thepharmaceutically active agent present in the second layer can be thesame. Alternatively, they can be different so that a firstpharmaceutically active agent is present in the microparticles in thefirst layer and a second, different pharmaceutically active agent ispresent in the second layer. Furthermore, the first layer can furthercomprise another pharmaceutically active agent, which can be in freeform or present within microparticles. Furthermore, the pharmaceuticallyactive agent disposed in the second layer optionally can be present in asecond population of controlled release microparticles.

The composition is multilayered and can comprise two, three, four ormore different layers. In one embodiment, the first layer is adjacentthe second layer. As such, the two layers can form a bilayercomposition. In another embodiment, the composition comprises a thirdlayer, that can be adjacent the first layer, adjacent the second layer,or is disposed between the first layer and the second layer.

At least one pharmaceutically active agent present in the second layeris initially (for example, within the first 15 minutes or within thefirst 30 minutes after exposure to an aqueous environment) released at afaster rate than the pharmaceutically active agent in the first layer.This can be achieved via a number of approaches. For example, thepharmaceutically active agent in the first layer is disposed incontrolled release microparticles whereas the pharmaceutically activeagent in the second layer is not present within or otherwise associatedwith controlled release microparticles. Furthermore, the first layer cancomprise a first controlled release matrix whereas the second layer cancomprise an immediate release matrix. Alternatively, the first layer cancomprise a first controlled release matrix whereas the second layercomprises a second, different controlled release matrix, wherein thefirst controlled release matrix has slower release kinetics than thesecond controlled release matrix. It is understand that a particulardosage form will vary depending upon the pharmaceutically active agentor agents to be delivered and the release profile desired for eachpharmaceutically active agent.

A variety of superabsorbent materials can be used in the practice of theinvention. The superabsorbent material can be polymeric, which caninclude, for example, polysaccharides, polysaccharide derivatives, andsynthetic polymers. Exemplary polymers include, for example, a starchgraft copolymer, a cross-linked carboxymethylcellulose derivative, across-linked hydroxypropyl distarch phosphate, a hydrolyzedstarch-acrylonitrile graft copolymer and a neutralized starch-acrylicacid graft copolymer, polyacrylic acid, polyacrylamido methylpropanesulfonic acid, polyvinyl acetic acid, polyvinyl phosphonic acid,polyvinyl sulfonic acid, isobutylene-maleic anhydride copolymer,carboxymethyl cellulose, alginic acid, carrageenan, polyaspartic acid,polyglutamic acid, polyvinyl amine, polydiallyl dimethyl ammoniumhydroxide, polyacrylamidopropyl trimethyl ammonium hydroxide, polyaminopropanol vinyl ether, polyallylamine, chitosan, polylysine,polyglutamine, polycarbophil, polycarbophilic calcium, polymethacrylicacid, polyacrylic acid, and mixtures thereof. In a preferred embodiment,the superabsorbent material is polycarbophil.

The superabsorbent material can constitute from about 1% to about 70%(w/w) of the layer in which it is present (e.g., the first layer, thesecond layer, or both the first and second layers or the optional thirdlayer) or from about 4% to about 50% (w/w) of the layer in which it ispresent (e.g., the first layer, the second layer, or both the first andsecond layers or the optional third layer).

As discussed above, the first layer, the second layer, or both the firstand second layers may further comprise a controlled release agent.Exemplary controlled release agents include, for example, acetatesuccinate, a polyvinyl derivative, polyethylene oxide, polyacrylic acid,modified starch, cross-linked high amylose starch, hydroxypropyl starch,hydroxypropyl methylcellulose phthalate, cellulose, microcrystallinecellulose, carboxymethylethyl cellulose, cellulose acetate,methylcellulose, ethylcellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, cellulose phthalate, cellulose acetate,cellulose acetate phthalate, cellulose acetate propionate, celluloseacetate succinate, cellulose acetate butyrate, cellulose acetatetrimellitate, poloxamer, povidone, alginic acid, sodium alginate,polyethylene glycol, polyethylene glycol alginate, gums (for example,xanthan gums), polymethacrylate, a copolymer of methacrylic acid andethyl acrylate, a copolymer of polymethyl vinyl ether and malonic acidanhydride, a copolymer of polymethyl vinyl ether and malonic acid or theethyl-, isopropyl-, n-butylesters thereof, zein, and mixtures of any ofthe foregoing. Furthermore, the first layer, the second layer or boththe first and second layers can further comprise a diluent, a lubricant,a glidant, or a mixture thereof. The second layer can further comprise adisintegrant. Disintegrants preferably are omitted from the first layer,because when intact compositions are exposed to an aqueous environment,disintegrants in the first layer may cause the first layer to breakapart thereby permitting the superabsorbent material to prematurelyswell and create a hard gel.

It is understood that the composition can further comprise a coatingthat encapsulates the first layer and the second layer. The coating canbe a non-functional (aesthetic coating) or can be a functional coating.Exemplary functional coatings include a controlled released coating,(for example, a delayed release coating, such as an enteric coating), amoisture barrier, or a taste masking film. The controlled releasecoating can include a controlled release agent and/or can be acontrolled release film coating.

The controlled release microparticles present in the first layer andoptionally present in the second layer can comprise a controlled releaseagent (for example, cross-linked high amylose starch sold under theTradename CONTRAMID® from Labopharm, Inc., Laval, Canada) that controlsthe release of the pharmaceutically active agent disposed therein and/ora controlled release coating or film. The microparticles have an averagediameter in the range from about 1 μm to about 1000 μm. Themicroparticles, due to their small size and high radius of curvature,resist crushing if the formulation is crushed, for example, with aconventional pill crusher or between spoons or in a pestle and mortar.In one embodiment, the microparticles have an average diameter in therange from about of 200 μm to about 900 μm, or from about 300 μm toabout 800 μm. The microparticles under certain circumstances have anaverage diameter of about 700 μm. In another embodiment, the controlledrelease microparticles have an average diameter in the range of fromabout 1 μm to about 400 μm, from about 5 μm to about 300 μm, or fromabout 10 μm to about 200 μm. The microparticles can have an averagediameter of about 100 μm. The controlled release microparticles includedin the first layer and optionally in the second layer can be coated withone or more controlled release films.

The compositions of the invention have certain properties. For example,in certain embodiments, when the composition is crushed and exposed to900 mL of water in a U.S.P. Type I Apparatus with stirring at 100 rpmfor 30 minutes at 37° C., less than about 50% by weight or optionallyless than about 25% by weight of the pharmaceutically active agentoriginally present in the composition before it was crushed broken isreleased into the water. Alternatively or in addition, when thecomposition is crushed and exposed to 900 mL of an aqueous solutioncontaining 60% (v/v) ethanol in a U.S.P. Type 1 Apparatus with stirringat 100 rpm for 30 minutes at 37° C., less than about 50% by weight oroptionally less than about 25% by weight of the pharmaceutically activeagent originally present in the composition before it was broken isreleased into the aqueous solution.

It is understood that the oral dosage forms of the invention can be inthe form of a capsule, caplet, pill, or a compressed tablet.

In another aspect, the invention provides a method of providingcontrolled release of a pharmaceutically active agent to a mammal, forexample, a human. The method comprises orally administering to anindividual in need of the pharmaceutically active agent one or more ofthe controlled release compositions described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of theinvention will become apparent from the following description ofpreferred embodiments, as illustrated in the accompanying drawings. Likereferenced elements identify common features in the correspondingdrawings. The drawings are not necessarily to scale, with emphasisinstead being placed on illustrating the principles of the presentinvention, in which:

FIGS. 1 A-D show schematic representations of exemplary misusepreventative, controlled release compositions. In FIGS. 1A and 1B, thecompositions are uncoated bilayers; in FIGS. 1C and 1D, the compositionsare coated bilayers. In FIGS. 1A and 1C, controlled releasemicroparticles containing a pharmaceutically active agent are disposedwithin a first layer (FIGS. 1A and 1C), and a pharmaceutically activeagent, which can be the same or different, is disposed within a secondlayer of the bilayer composition. In FIGS. 1B and 1D, the second layerof the bilayer compositions also comprise microparticles containing apharmaceutically active agent, which can be the same as or different tothe pharmaceutically active agent in the microparticles disposed withinthe first layer.

FIGS. 2A-B show schematic representations of exemplary misusepreventative, controlled release formulations which are similar to thosepresented in FIGS. 1C and 1D, except the coatings are functionalcoatings, for example, a controlled release coating achievable by one ormore of the following—a controlled release film, a controlled releaseagent, and controlled release microparticles. In FIG. 2A, controlledrelease microparticles containing a pharmaceutically active agent aredisposed within the first layer, and in FIG. 2B the controlled releasemicroparticles are present within both the first layer and the secondlayer.

FIGS. 3A and 3B are graphs showing the in vitro dissolution profile ofoxycodone HCl (FIG. 3A) and acetaminophen (FIG. 3B) from an intact,exemplary controlled release formulation of the invention in a U.S.P.Type III Apparatus. FIG. 3A shows the release profile of oxycodone HClin potassium phosphate buffer at pH 6.8 for 12 hours (-Δ-), 0.1 Mhydrochloric acid at pH 1.2 for 12 hours (--), 0.1 M hydrochloric acidat pH 1.2 for 1 hour followed by potassium phosphate buffer pH 6.8 for11 hours (-▪-), and 40% ethanol (-▾-). FIG. 3B shows the release profileof acetaminophen in potassium phosphate buffer at pH 6.8 for 12 hours(-Δ-), 0.1 M hydrochloric acid at pH 1.2 for 12 hours (--), 0.1 Mhydrochloric acid at pH 1.2 for 1 hour followed by potassium phosphatebuffer at pH 6.8 for 11 hours (-▪-), and 40% ethanol (-▾-).

FIGS. 4A and 4B are graphs showing the in vitro dissolution profile ofoxycodone HCl from half tablets (FIG. 4A) and quarter tablets (FIG. 4B)of three lots of an exemplary controlled release formulation of theinvention in a U.S.P. Type I Apparatus in potassium phosphate buffer atpH 6.8.

FIGS. 5A and 5B are graphs showing the in vitro dissolution profile ofacetaminophen from half tablets (FIG. 5A) and quarter tablets (FIG. 5B)of three lots of an exemplary controlled release formulation of theinvention in a U.S.P. Type I Apparatus in potassium phosphate buffer atpH 6.8.

FIGS. 6A and 6B are graphs showing the in vitro dissolution profile ofoxycodone HCl (FIG. 6A) and acetaminophen (FIG. 6B) from a crushed,exemplary controlled release formulation of the invention in a U.S.P.Type I Apparatus. FIG. 6A shows the release profile of oxycodone HCl inacidified potassium phosphate aqueous solution at pH 3.0 (-□-),potassium phosphate buffer at pH 6.8 (-▴-), basified potassium phosphateaqueous solution at pH 10.0 (-⋄-), water (--), 20% ethanol (-∇-), and40% ethanol (-♦-). FIG. 6B shows the release profile of acetaminophen inacidified potassium phosphate aqueous solution at pH 3.0 (-□-),potassium phosphate buffer pH 6.8 (-▴-), basified potassium phosphateaqueous solution at pH 10.0 (-⋄-), and water (--).

FIGS. 7A and 7B are graphs showing the in vitro dissolution profile ofoxycodone HCl (FIG. 7A) and acetaminophen (FIG. 7B) from an intact,exemplary controlled release formulation of the invention in a U.S.P.Type III Apparatus. FIG. 7A shows the release profile of oxycodone HClin 0.1 M hydrochloric acid at pH 1.2 for 12 hours (--), potassiumphosphate buffer pH 6.8 for 12 hours (-Δ-), and 0.1 M hydrochloric acidat pH 1.2 for 1 hour followed by potassium phosphate buffer pH 6.8 for11 hours (-▪-). FIG. 7B shows the release profile of acetaminophen in0.1 M hydrochloric acid at pH 1.2 for 12 hours (--), potassiumphosphate buffer pH 6.8 for 12 hours (-Δ-), and 0.1 M hydrochloric acidat pH 1.2 for 1 hour followed by potassium phosphate buffer pH 6.8 for11 hours (-▪-).

FIGS. 8A and 8B are graphs showing the in vitro dissolution profile ofoxycodone HCl (FIG. 8A) and acetaminophen (FIG. 8B) from a crushed,exemplary controlled release formulation of the invention in a U.S.P.Type I Apparatus. FIG. 8A shows the release profile of oxycodone HCl inpotassium phosphate buffer pH 6.8 (-Δ-), and 0.1 M hydrochloric acid atpH 1.2 (--). FIG. 8B shows the release profile of acetaminophen inpotassium phosphate buffer pH 6.8 (-Δ-), and 0.1 M hydrochloric acid atpH 1.2 (--).

FIG. 9 is a graph showing the in vitro dissolution profile of a coatedbilayer embodiment containing 20 mg oxycodone HCl/650 mg acetaminophen,where the release of oxycodone was measured in a U.S.P. Type IIIApparatus at 100 rpm for twelve hours in 0.1 M hydrochloric acid at pH1.2 for 1 hour and then in potassium phosphate buffer pH 6.8 for 11hours.

FIGS. 10A and 10B are graphs showing the in vitro dissolution profile ofoxycodone HCl (FIG. 10A) and acetaminophen (FIG. 10B) from an intact,exemplary controlled release formulation of the invention in a U.S.P.Type III Apparatus. FIG. 10A shows the release profile of oxycodone HClin potassium phosphate buffer pH 6.8 (--). FIG. 10B shows the releaseprofile of acetaminophen in potassium phosphate buffer pH 6.8 (--).

FIGS. 11A and 11B are graphs showing the in vitro dissolution profile ofoxycodone HCl (FIG. 11A) and acetaminophen (FIG. 11B) from a crushed,exemplary controlled release formulation of the invention in a U.S.P.Type I Apparatus. FIG. 11A shows the release profile of oxycodone HCl inpotassium phosphate buffer pH 6.8 (--), and FIG. 11B shows the releaseprofile of acetaminophen in potassium phosphate buffer pH 6.8 (--).

FIG. 12 is a graph showing the in vitro dissolution profile ofmethylphenidate from four intact, exemplary controlled releaseformulations of the invention in a U.S.P. Type II Apparatus in acidifiedwater, pH 3.5.

FIGS. 13A and 13B are graphs showing the in vitro dissolution profile ofoxycodone HCl (FIG. 13A) and acetaminophen (FIG. 13B) from three intactexemplary controlled release formulations of the invention in a U.S.P.Type III Apparatus in phosphate buffer, pH 6.8.

FIGS. 14A and 14B are graphs showing the in vitro dissolution profilesof oxycodone HCl (FIG. 14A) and acetaminophen (FIG. 14B) from uncoatedcrushed exemplary controlled release formulations of the invention asmeasured in a U.S.P. Type I Apparatus in potassium phosphate buffer pH1.2 (--), pH 6.8 (-□-), and pH 10 (-▾-), in water (-▴-), and in 40%ethanol (-♦-).

FIGS. 15A and 15B are graphs showing the in vitro dissolution profilesof oxycodone HCl (FIG. 15A) and acetaminophen (FIG. 15B) from whole andbisected exemplary controlled release formulations of the invention asmeasured in a U.S.P. Type III Apparatus. FIG. 15A shows the releaseprofiles of oxycodone HCl in whole tablets in phosphate buffer pH 6.8(-▪-), whole tablets in 40% ethanol (-♦-), bisected tablets in phosphatebuffer pH 6.8 (--), and bisected tablets in 40% ethanol (-Δ-). FIG. 15Bshows the release profiles of acetaminophen in whole tablets inphosphate buffer pH 6.8 (-▪-), whole tablets in 40% ethanol (-♦-),bisected tablets in phosphate buffer pH 6.8 (--), and bisected tabletsin 40% ethanol (-Δ-).

FIG. 16 is a graph showing the in vitro dissolution profiles ofoxycodone HCl (--) and acetaminophen (-o-) from intact exemplarycontrolled release formulations of the invention as measured in a U.S.P.Type III Apparatus for 1 hour in acid medium, pH 1.2, followed by 11hours in phosphate buffer, pH 6.8.

FIG. 17 is a graph showing the in vitro dissolution profiles ofoxycodone HCl (--) and acetaminophen (-o-) from crushed exemplarycontrolled release formulations of the invention as measured in a U.S.P.Type I Apparatus in deionized water.

DETAILED DESCRIPTION OF THE INVENTION

The invention is based, in part, upon the discovery that it is possibleto produce a controlled release platform that renders pharmaceuticalcompositions less susceptible to intentional abuse and accidental misusethan other controlled release compositions, while being free fromnoxious additives, active ingredient antagonists, prodrugs and the like.The formulations maintain their controlled release properties whenbisected (broken in half) as can occur when a patient or care-giverbreaks a tablet in half to make the tablet easier to swallow. Even whencrushed, the compositions of the invention prevent dose dumping becausethe microparticles contained within the composition remain substantiallyintact and retain their controlled release properties. The crushedformulations cannot easily be administered intravenously via a syringebecause of hard gel formation, and if crushed and administered nasally,they swell causing an unpleasant sensation.

In one aspect, the invention provides a controlled release multilayercomposition comprising: (a) a first layer comprising a first populationof controlled release microparticles having a pharmaceutically activeagent disposed therein; (b) a second layer comprising a pharmaceuticallyactive agent disposed therein; and (c) a superabsorbent material (e.g.,polycarbophil) disposed within the first layer, the second layer, orboth the first layer and the second layer. In another aspect, theinvention provides a controlled release multilayer compositioncomprising: (a) a first layer comprising a superabsorbent material (forexample, polycarbophil) and a plurality of controlled releasemicroparticles having at least one pharmaceutically active agentdisposed therein. The second layer comprises a pharmaceutically activeagent that can be the same as or different from the pharmaceuticallyactive agent present in the microparticles of the first layer. In eachaspect of the invention, the first and second layers can be encapsulatedwith either a non-functional coating or a functional coating. When thecompositions are crushed, the microparticles remain substantially intactand control the release of the pharmaceutically active agent disposedtherein and prevent dose dumping. As used herein, the term “dosedumping” is understood to mean an uncontrolled release of apharmaceutically active agent where at least 80% of the pharmaceuticallyactive agent in the formulation is released within 30 minutes (aspecification that can be used to characterize a formulation as animmediate release formulation).

FIGS. 1A-D and 2A-B show certain embodiments of the oral dosageformulation of the invention. Each exemplary formulation contains abilayer composition 10 having a first layer 20 and a second layer 30. Ineach formulation, the first layer contains a plurality of controlledrelease microparticles 40 that comprise a pharmaceutically active agent.The second layer of each formulation contains a second pharmaceuticallyactive agent 50, which can be the same or different as thepharmaceutically active agent present in the microparticles in the firstlayer. Either the first layer, the second layer, or both the first andsecond layers can contain a superabsorbent material. In FIGS. 1B and 1D,the second layer also contains controlled release microparticles 40′,which may be the same as or different from microparticles 40 disposed inthe first layer 10. In the embodiments shown in FIGS. 1A and 1B, thebilayer is not coated; however, in the embodiments shown in FIGS. 1C and1D, the bilayers are encapsulated in a coat, for example, anon-functional (aesthetic) coat. The embodiments depicted in FIGS. 2Aand 2B are similar to those depicted in FIGS. 1C and 1D except coating60 is a functional coating. As shown, the coating is a controlledrelease coating that is defined by a controlled release film, or is acoating containing a controlled release agent and/or controlled releasemicroparticles 40″, which can be the same as or different from thecontrolled release microparticles 40 disposed in first layer 20 or theoptional controlled release microparticles 40′ disposed in second layer30. In each of the embodiments shown in FIGS. 1A-D and 2A-B, themicroparticles control the release of the active ingredient irrespectiveof whether the tablet is intact or compromised (for example, bybisection or crushing). Furthermore, it is understood that theprinciples depicted in each of the figures can be present inmultilayered dosage forms that contain more than two layers.

In one embodiment, first layer 20 is a controlled release layer in whichthe microparticles 40 enable a controlled release of thepharmaceutically active agent from the formulation over a prolongedperiod of time. Layer 20 can also comprise or define a controlledrelease matrix. The superabsorbant material, which can be disposed inlayer 20, layer 30, or both layers 20 and 30 may also slow release ofthe pharmaceutically active agent, with minimal swelling upon contactwith aqueous media. However, when the composition is crushed, a greatersurface area of the superabsorbant material is exposed so that it swellsrapidly to form a hard gel upon contact with an aqueous solvent.

In one embodiment, second layer 30 is an immediate release layer whichallows for rapid disintegration and release of the secondpharmaceutically active agent 50. Agent 50 may be the same as ordifferent from agent 40. The second layer can also containmicroparticles 40′, which would provide delayed release of thepharmaceutically active agent disposed therein relative to the releaseof agent 50. In another embodiment, composition 10 may have a coating 60that contains microparticles 40″.

Under normal use, the compressed multilayered composition 10 has ahardness in the range of, for example, from about 100 N to about 500 N,such that the superabsorbent material in first layer 20, second layer30, or both first and second layers 20 and 30 is prevented fromabsorbing aqueous solvent. As a result, the composition, even whencombined with an aqueous solvent maintains sufficient integrity so thatthe majority of the superabsorbent material is prevented from swellingand disrupting the integrity of the multilayered composition.Furthermore, the resulting hardness renders the composition difficult tocrush. When combined with an aqueous solvent, the solvent graduallypermeates into both first layer 20 and second layer 30, and thepharmaceutically active agent present in second layer 30 is initiallyreleased faster than the pharmaceutically active agent present in themicroparticles in first layer 20. As used herein, the term “initiallyreleased” refers to the release of at least one pharmaceutically activeagent within 15 minutes or within 30 minutes after the composition hasbeen exposed to an aqueous solvent. However, when crushed and exposed toan aqueous solvent, the superabsorbent material swells to form a rigidgel that encapsulates the microparticles. It is understood that themicroparticles are a primary mechanism for controlling the release ofthe pharmaceutically active agent disposed therein. However, the hard,rigid gel that forms around the microparticles, along with otheringredients of the composition, can also impart controlled releaseproperties in addition to those provided by the microparticles.

It is contemplated that the compositions described herein can be usedfor the delivery of one or more (for example, two, three, four or more)pharmaceutically active agents. With respect to all the embodimentsdepicted in FIGS. 1A-D and 2A-B, it is understood, for example, thatmicroparticles 40 in first layer 20 can contain the samepharmaceutically active agent as the pharmaceutically active agent 50present in second layer 30. As a result, such a bilayer compositionpermits the creation of a desired release profile, for example, with afast initial release from second layer 30 followed by a slowersubsequent release from first layer 20. Alternatively, thepharmaceutically active agent present in the microparticles 40 in thefirst layer may be different from free pharmaceutically active agent 50in the second layer. For example, the pharmaceutically active agent inmicroparticles 40 in the first layer can be oxycodone whereas freepharmaceutically active agent 50 in second layer 30 can beacetaminophen. Furthermore, it is understood that the samepharmaceutically active agent in the second layer (for example,acetaminophen) can also be present in the free form (i.e., not includedin or associated with microparticles) in the first layer. Such anexample is depicted in Examples 1 and 2, wherein the microparticles inthe first layer contain oxycodone, and acetaminophen is present in freeform in both the first layer and the second layer.

In addition, it is contemplated that in the bilayer depicted in FIGS.1A-D and 2A-B, first layer 20 can contain or define a controlled releasematrix, whereas second layer 30 can define an immediate release matrix.Alternatively, first layer 20 and second layer 30 can both contain ordefine two different controlled release matrices. Furthermore, thecompositions can further contain a non-functional or aesthetic coating(see, FIGS. 1C and 1D) or a functional coating (see, FIGS. 2A and 2B).It is understood, however, that the compositions can vary depending uponwhat pharmaceutically active agent or agents are to be released and whatrelease profiles are desired for each agent.

In the case of an intact composition, when exposed to an aqueousenvironment (for example, a solution containing at least 10% (v/v)water), the pharmaceutically active agent disposed in the second layeris initially released (for example, within 15 minutes or within 30minutes after exposure to an aqueous solvent) at a faster rate than thepharmaceutically active agent disposed in the first layer. At least onepharmaceutically active agent is released from the intact formulationover a prolonged period of time (for example, for at least 6 hours, atleast 8 hours, at least 12 hours, at least 18 hours, or at least 24hours). In certain embodiments, at least 50%, preferably 60%, morepreferably 70%, and even more preferably 80% of at least onepharmaceutically active agent is prevented from being releasedsubstantially immediately (for example, within 30 minutes) from theintact composition when exposed to an extraction medium, for example,water, aqueous solutions ranging in pH from 1.2 to 6.8, and differentethanolic media (for example, water containing 20% ethanol, 40% ethanol,60% ethanol, or 80% ethanol and 100% ethanol).

When the oral dosage form of the invention is bisected, for example,axially bisected, as can happen when a patient breaks a tablet in halfto make it easier to swallow, the first and/or second layers becomecompromised to expose more superabsorbent material. However, based onthe hardness of the first layer, only a small amount of thesuperabsorbent material swells and the resulting portions of thebisected tablet maintain their integrity. As a result, the bisectedportions of the compositions of the invention have a release profile ofthe pharmaceutically active agent substantially the same as the intactcomposition. These principles are demonstrated, for example, in Example1 and FIGS. 3-5 where the superabsorbent material is disposed within thefirst layer. Furthermore, even when bisected, the formulations of theinvention permit the release of the pharmaceutically active agent overat least 6 hours, at least 12 hours, at least 18 hours, or over at least24 hours. In certain embodiments, at least 50%, preferably 60%, morepreferably 70%, and even more preferably 80% of at least onepharmaceutically active agent is prevented from being releasedsubstantially immediately (for example, within 30 minutes) from theformulation when exposed to an extraction medium, for example, water,aqueous solutions ranging in pH from 1.2 to 6.8, and different ethanolicmedia (for example, water containing 20% ethanol, 40% ethanol, 60%ethanol, or 80% ethanol and 100% ethanol).

When the oral dosage form of the invention is crushed (for example, witha commercially available pill crusher to break formulation into at least10 particles or more) and then exposed to an aqueous environment, thesuperabsorbent material swells rapidly (for example, within about 30seconds) to create a hard gel that traps the microparticles. Based inpart upon their small size (high radius of curvature), themicroparticles resist the crushing process and remain substantiallyintact. The hard gel provides an unpleasant experience if the crushedcomposition is snorted up a nostril and gel formation occurs within thenostril. This process has the advantage that the nasal secretions neededfor absorption of the active ingredient into the blood-stream areabsorbed by the superabsorbent material preventing intoxication via thisroute. Similarly, if the composition is crushed and exposed to anaqueous environment to extract the pharmaceutically active agent, thesuperabsorbant material in the core can absorb the extraction mediumleaving little or no extraction medium to administer. In addition, thehard gel that is formed during this process cannot be drawn or pushedthough a syringe needle.

In the case of compositions that have a controlled release coating, thecoatings may be compromised by crushing. However the microparticlesstill permit the controlled release of the pharmaceutically active agentand prevent the pharmaceutically active agent from being releasedsubstantially immediately from the formulation (i.e., the microparticlesprovide controlled release of the pharmaceutically active agent) and thegel forms to entrap the microparticles. For example, at least 50%,preferably 60%, more preferably 70%, and even more preferably 80% of atleast one pharmaceutically active agent is prevented from being releasedsubstantially immediately (for example, within 30 minutes) from theformulation (see, FIG. 6A, which is discussed in Example 1). As aresult, the compositions of the invention prevent dose dumping in water,20% ethanol, 40% ethanol, and 60% ethanol even if the formulations havebeen broken or crushed.

In certain embodiments, the compositions of the invention, when crushedand exposed to 900 mL of water in a U.S.P. Type I Apparatus withstirring at 100 rpm for 30 minutes at 37° C., less than about 50%, lessthan about 45%, less than about 40%, less than about 35%, less thanabout 30%, less than about 25%, or less than about 20% by weight of atleast one pharmaceutically active agent originally present in theformulation before it was crushed is released into the water. In certainother embodiments, when the formulation of the invention is crushed andexposed to 900 mL of an aqueous solution containing 60% (v/v) ethanol ina U.S.P. Type I Apparatus with stirring at 100 rpm for 30 minutes at 37°C., less than about 50%, less than about 45%, less than about 40%, lessthan about 35%, less than about 30%, less than about 25%, or less thanabout 20% by weight of at least one pharmaceutically active agentoriginally present in the formulation before it was broken is releasedinto the aqueous solution.

Each of the components of the formulation of the invention are discussedin the following sections.

A. Considerations for a Multilayer Component

It is understood that the multilayer can include two, three, four ormore different layers. In one embodiment, the multilayer is a bilayer,where the first layer and the second layer are adjacent one another. Inanother embodiment, the compositions can comprise a third layer, whichcan be located adjacent the first layer, adjacent the second layer, ordisposed between the first and second layers.

The first layer comprises a first population of controlled releasemicroparticles having at least one pharmaceutically active agentdisposed therein. The second layer comprises a pharmaceutically activeagent disposed therein, which can be the same as or different from thepharmaceutically active agent in the microparticles disposed in thefirst layer. The first layer, the second layer, both the first andsecond layers, or an optional third layer can comprise a superabsorbentmaterial. The pharmaceutically active agent disposed in the second layeris initially released at a faster rate than the pharmaceutically activeagent disposed within the microparticles in the first layer. This can beachieved in a number of different ways, which include having at leastone pharmaceutically active agent in the microparticles in the firstlayer but not the second layer. In addition, the first layer cancomprise a controlled release agent or define a controlled releasematrix whereas the second layer can define an immediate release matrix.Alternatively, the first layer and the second layers can both comprise acontrolled release agent or define a controlled release matrix, but thecompositions of each can be chosen so that pharmaceutically activeagents are initially released from the second layer at a faster ratethan from the first layer.

The term “superabsorbent material,” as used herein is understood to meanany material that absorbs solvent, for example, 1 gram of materialabsorbs at least 30 mL, more preferably 50 mL of solvent, which, uponabsorption of the solvent, swells to produce a hydrated gel (hydrogel).In general, useful superabsorbent materials, when exposed to an aqueousmedium (for example, water), absorb in excess of 10-15 times, such as atleast greater than 30 times, more preferably 50 times, of water based onits own weight. In certain embodiments, the superabsorbent material is apolymer.

Superabsorbent materials can be manufactured from polysaccharidederivatives or cross-linked polyelectrolytes. Polysaccharidesuperabsorbents include, but are not limited to, a starch graftcopolymer, a crosslinked carboxymethylcellulose derivative, a hydrolyzedstarch-acrylonitrile graft copolymer and a neutralized starch-acrylicacid graft copolymer. Cross-linked polyelectrolytes can containfunctional groups such as carboxyl, sulfonate, sulphate, sulfite,phosphate, amine, imine, amide, quaternary ammonium or a mixturethereof. Examples of polyelectrolyte polymers include, but are notlimited to, salts or partial salts of polyacrylic acid, polyacrylamidomethylpropane sulfonic acid, polyvinyl acetic acid, polyvinyl phosphonicacid, polyvinyl sulfonic acid, an isobutylene-maleic anhydridecopolymer, carboxymethyl cellulose, alginic acid, carrageenan,polyaspartic acid, polyglutamic acid, polyvinyl amine, polydiallyldimethyl ammonium hydroxide, polyacrylamidopropyl trimethyl ammoniumhydroxide, polyamino propanol vinyl ether, polyallylamine, chitosan,polylysine, polyglutamine and copolymers or mixtures thereof

Exemplary superabsorbent materials can include a polymer selected fromthe group consisting of polycarbophil, polycarbophilic calcium,polymethacrylic acid, polyacrylic acid, and mixtures thereof.Polycarbophil is a superabsorbent polymer is capable of absorbing andretaining large quantities of water. Polycarbophil is a high molecularweight acrylic acid polymer cross-linked with divinyl glycol, and issold under the tradename, NOVEON® AA-1, by Lubrizol Corporation OH, USA.It is understood that 1 gram of polycarbophil can absorb about 62 gramsof water. Polycarbophil is stable and does not undergo hydrolysis oroxidation under normal conditions. Calcium salts of polycarbophil(polycarbophilic calcium) can be used and are available commerciallyunder the tradename NOVEON® CA-1 or CA-2 from Lubrizol Corporation OH,USA. Other exemplary superabsorbent materials include Carbopol®polymers, which are acrylic acid polymers cross-linked with, forexample, allyl ethers of pentaerythritol, for example, Carbopol® 71G (acarbomer homopolymer type A), Carbopol® 971P (a carbomer homopolymertype A), and Carbopol® 974 (a carbomer homopolymer type B), each ofwhich is available from Lubrizol Corporation, OH, USA.

The superabsorbent material provides two functions. First, when thecomposition containing the superabsorbent material (for example,polycarbophil) is crushed and combined with solvent (for example, water)for parenteral injection, the superabsorbent material rapidly absorbswater, swells and forms a hard gel thus preventing injection. Inaddition, depending upon the amount of solvent added, all of the solventmay be absorbed leaving no residual solvent that can be administered.Second, if the composition is crushed and snorted into a nostril thesuperabsorbent material absorbs the liquid in the nostril causing thesuperabsorbent material to swell. Not only does the swelling causediscomfort but also prevents the drug disposed within the formulationfrom being rapidly released (for example, within less than 30 minutes).

In general, the proportion of the superabsorbent material in the firstlayer varies from about 1% (w/w) to about 70% (w/w) of the first layer,more preferably from about 2% (w/w) to about 50% (w/w) of the firstlayer. Furthermore, the superabsorbent material in the first layervaries from about 3% (w/w) to about 20% (w/w) of the final intactcomposition, more preferably from about 4% (w/w) to about 14% (w/w) ofthe final intact composition, more preferably from about 4% (w/w) toabout 10% (w/w) of the final intact formulation.

Compositions of exemplary controlled release microparticles and methodsfor their manufacture are described in Section C below. In addition tothe superabsorbent material and the microparticles, the first layeroptionally further comprises or defines a controlled release matrix. Inaddition, depending up the circumstances, the second layer optionallyfurther comprises or defines either an immediate release matrix or acontrolled release matrix.

It is understood that materials that can be used to create a suitablecontrolled release matrix include, for example, acetyl succinate, apolyvinyl derivative (for example, polyvinyl alcohol, polyvinyl acetate,polyvinyl acetate phthalate, a copolymer of vinyl acetate and vinylpyrrolidone, a copolymer of vinyl acetate and crotonic acid,polyvinylpyrollidone), polyethylene oxide, polyacrylic acid,polysaccharides (for example, modified starch, cross-linked high amylosestarch, hydroxypropyl starch, hydroxypropyl methylcellulose phthalate,cellulose and cellulose derivatives (for example, microcrystallinecellulose, carboxymethylethyl cellulose, cellulose acetate,methylcellulose, ethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, cellulose phthalate, cellulose acetate,cellulose acetate phthalate, cellulose acetate propionate, celluloseacetate succinate, cellulose acetate butyrate, cellulose acetatetrimellitate), poloxamer, povidone, alginic acid, sodium alginate,polyethylene glycol, polyethylene glycol alginate, gums (for example,xanthan gum), polymethacrylates (including, for example, a copolymer ofmethacrylic acid and methyl-methacrylate, and a copolymer of methacrylicacid and ethyl acrylate), a copolymer of polymethyl vinyl ether andmalonic acid anhydride, a copolymer of polymethyl vinyl ether andmalonic acid or the ethyl-, isopropyl-, n-butylesters thereof, zein, andmixtures of the foregoing.

It is understood that materials that can be used to create an immediaterelease matrix include, for example, microcrystalline cellulose, calciumphosphates (monobasic, dibasic and or tribasic), saccharides such aslactose, sucrose, dextrins, superdisintegrants such as croscarmalosesodium, sodium starch glycolate, and crospovidone.

In addition, the first layer and the second layer can comprise otherexcipients and manufacturing aids including, for example, one or moreof, a diluent (for example, microcrystalline cellulose, lactose,dicalcium phosphate, sucrose), a lubricant (for example, sodium stearylfumarate, magnesium stearate, calcium stearate, stearic acid,hydrogenated vegetable oils), a glidant (for example, colloidal silicondioxide and talc), a dye (for example, iron oxide), and a filler (forexample, lactose, pregelatinized starch, dextrin, maltose, calciumphosphates (monobasic, dibasic and/or tribasic), microcrystallinestarch).

In addition, the second layer optionally includes a disintegrant tofacilitate disintegration of the second layer. The disintegrants,however, typically are not included in the first layer so as to minimizethe risk that the first layer disintegrates upon exposure to an aqueousmedia to expose the bulk of the superabsorbent material. It is preferredthat the first layer remain intact when exposed to an aqueousenvironment. Useful disintegrants include, for example, crospovidone,sodium starch glycolate, sodium alginate, and croscarmellose.

B. Considerations for the Coat

It is understood that the multilayered composition as described inSection A can further comprise a coat (for example, a non-functional(aesthetic) coating as shown in FIGS. 1C and 1D or a functional coating(for example, a controlled release coat as shown in FIGS. 2A and 2B)).Under normal use, the coat still provides a rigid net-like structurethat encapsulates the multilayer and can help minimize the swelling ofthe superabsorbent material.

Exemplary non-functional coatings include, for example, an aqueous basedshellac dispersion MARCOAT 125® from Innovative Material Technologies,an aqueous dispersion of ethyl cellulose AQUACOAT® from FMC Biopolymers,methacrylic acid/ethyl acrylate copolymers KOLLICOAT® from BASF,hydroxypropylcellulose KLUCEL® from Aqualon, modified peas starch basedaqueous film coating system LYCOAT® from Roquette, hydroxypropylmethylcellulose acetate succinate AQOAT® (HPMCAS) from Shin-Etsu, andOPADRY®, OPADRY™®, OPADRY FX®, OPALUX®, OPAGLOS®, Ethocel® 10, 45, 100cps (ethyl cellulose) all from Colorcon (PA, USA)

It is understood, however, that the coating can be a functional coating.In other words, the coating provides a function beyond aesthetics, whichcan include, for example, controlled release (such as delayed release)of an agent disposed within the composition, a moisture barrier, and ataste masking film.

The controlled release coatings can resist the release of drug as the pHof the extraction media varies (for example, when the formulations arecombined with conventional carbonated beverages). Furthermore, thecontrolled release coatings can resist the release of drug in thepresence of alcohol in the extraction media even at levels that exceedthe alcohol content of alcoholic beverages.

In certain embodiments, the controlled release coating comprises acontrolled release agent. Alternatively, or in addition, the coat is acontrolled release film. Exemplary controlled release agents andfilm-coatings can be selected from the group consisting of acetylsuccinate, a polyvinyl derivative (for example, polyvinyl alcohol,polyvinyl acetate, polyvinyl acetate phthalate, a copolymer of vinylacetate and vinyl pyrrolidone, a copolymer of vinyl acetate and crotonicacid, polyvinylpyrollidone), polyethylene oxide, polyacrylic acid,polysaccharides (for example, modified starch, cross-linked high amylosestarch, hydroxypropyl starch, hydroxypropyl methylcellulose phthalate,cellulose and cellulose derivatives (for example, microcrystallinecellulose, carboxymethylethyl cellulose, cellulose acetate,methylcellulose, ethylcellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, cellulose phthalate, cellulose acetate,cellulose acetate phthalate, cellulose acetate propionate, celluloseacetate succinate, cellulose acetate butyrate, cellulose acetatetrimellitate)), poloxamer, povidone, alginic acid, sodium alginate,polyethylene glycol, polyethylene glycol alginate, gums (for example,xanthan gum), polymethacrylates (including, for example, a copolymer ofmethacrylic acid and methyl-methacrylate, and a copolymer of methacrylicacid and ethyl acrylate), a copolymer of methacrylic acid and ethylacrylate, a copolymer of polymethyl vinyl ether and malonic acidanhydride, a copolymer of polymethyl vinyl ether and malonic acid or theethyl-, isopropyl-, n-butylesters thereof, zein, and mixtures of theforegoing.

Further examples of controlled release film-coating polymers include,but are not limited to, methylcellulose, ethylcellulose (for example,Aquacoat® type from FMC Corp.), methylhydroxyethylcellulose,methylhydroxypropylcellulose (for example, Pharmacoat® type from ShinEtsu Corp.), ethylhydroxyethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, carboxymethylcellulose ormethylcarboxymethylcellulose, acrylic polymers, polyvinylacetates,polyvinyl chlorides, polymethylmetacrylates or a terpolymer ofvinylchloride, vinylalcohol and vinylacetate,hydroxypropylmethylcellulose phthalate (for example, HP type from ShinEtsu), hydroxypropylmethylcellulose acetate succinate (for example,Aqoat from Shin Etsu), cellulose acetate phthalate (for example,Aquacoat CPD from FMC Corp. or C-A-P NF from Eastman Chemical),polyvinyl acetate phthalate (for example, Sureteric from Colorcon),carboxymethylethylcellulose, and co-polymerized methacrylicacid/methacrylic acid methyl esters (for example, Eudragit fromDegussa/Evonik Industries or Kollicoat from BASF or Acryl-Eze fromColorcon or Eastacryl from Eastman Chemical).

For example, Kollidon® SR (a powder consisting of polyvinyl acetate (8parts, w/w) and polyvinyl pyrrolidone (2 parts, w/w)) can be used incombination with xanthan gum. Kollidon® SR is available from BASF, ON,Canada. Alternatively, the coat can be, for example, Eudragit® L30D 55,available from Degussa/Evonik Industries, NJ, USA. Furthermore, it isunderstood that, depending upon the release kinetics desired, the samecontrolled release agents and coatings can be disposed within or cancoat the microparticles described below in Section C.

Exemplary moisture barriers include, for example, Opadry™ AqueousMoisture Barrier (AMB), high performance Opadry II (Colorcon, Pa., USA).

Exemplary taste masking films include, for example, Opadry™ (Colorcon,Pa., USA).

In addition, the coating can comprise one or more of a viscosityincreasing agent (for example, xanthan gum, polyethylene oxide,polyvinylpyrollidone, cellulose and sucrose derivatives), a lubricant(for example, sodium stearyl fumarate, magnesium stearate and stearicacid), a glidant (for example, colloidal silicon dioxide and talc), anda dye (for example, iron oxide). In addition, the coating can comprise aplasticizer. Examples of plasticizers include, but are not limited to,cetanol, triacetin, citric acid esters, phthalic acid esters, dibutylsuccinate, acetylated monoglyceride, acetyltributyl, acetyltributylcitrate, acetyltriethyl citrate, benzyl benzoate, calcium stearate,castor oil, chlorebutanol, colloidal silica dioxide, dibutyl phthalate,dibutyl sebacate, diethyl oxalate, diethyl malate, diethyl maleate,diethyl malonate, diethyl fumarate, diethyl phthalate, diethyl sebacate,diethyl succinate, dimethylphthalate, dioctyl phthalate, glycerin,glyceroltributyrate, glyceroltriacetate, glyceryl behanate, glycerylmonostearate, hydrogenated vegetable oil, lecithin, leucine, magnesiumsilicate, magnesium stearate, polyethylene glycol, propylene, glycol,polysorbate, silicone, stearic acid, talc, titanium dioxide, triacetin,tributyl citrate, triethyl citrate, zinc stearate, PEG (polyethyleneglycol), and the like.

In addition, the coat can comprise controlled release microparticlescontaining a pharmaceutically active agent of interest. Compositions ofexemplary controlled release microparticles and methods for theirmanufacture are described in the following section.

C. Considerations for the Controlled Release Microparticles

As shown in FIGS. 1A-D and 2A-B, the compositions of the inventioncomprise controlled release microparticles disposed within at least onelayer of the multilayered composition (see, FIGS. 1A, 1C and 2A), twolayers of the multilayered composition (see, FIGS. 1B, 1D and 2B), orwithin the controlled release coating (see, FIGS. 2A and 2B).

The controlled release microparticles contain a pharmaceutically activeagent and facilitate the controlled release of the pharmaceuticallyactive agent disposed therein. Depending upon the configuration chosen,the formulations can release the pharmaceutically active agent over aprolonged period of time, for example, at least 6 hours, at least 8hours, at least 12 hours, at least 18 hours, or at least 24 hours.

Although the controlled release particles may take a variety of forms,they have a number of features in common, which include (i) they havecontrolled release properties and (ii) they are of a size that makesthem hard to crush even when the formulations are crushed with aconventional pill crusher or the like. The microparticles may have acore and a coat, where either or both provide controlled releaseproperties.

The core of the microparticles can comprise the pharmaceutically activeagent and a variety of excipients, which include, for example, one ormore of, a spheronizing agent, a plasticizer, and a controlled releaseagent. Exemplary spheronizing agents include, for example,microcrystalline cellulose, ethyl cellulose, low substitutedhydroxypropylcellulose and dicalcium phosphate dihydrate.Microcrystalline cellulose is preferred and is available commerciallyunder the tradename Avicel® PH101 from FMC BioPolymer, DE, USA.Microcrystalline cellulose forms a plastic and cohesive mass uponwetting, which is desirable for the successful production of sphericalgranules. Microcrystalline cellulose is considered to aid thespheronization process by absorbing water like a molecular sponge andhelps in the binding and lubrication of the moistened powder mass duringextrusion. During the spheronization process, moisture trapped in themicrocrystalline cellulose microfibrils adds plasticity to the extrudateand helps convert short round extrudates obtained by extrusion intospherical pellets. Different grades of microcrystalline cellulose arecommercially available, and a preferred grade suitable forextrusion-spheronization is Avicel® PH 101, because of its smallparticle size, low packing density and high water retentive capacity.

In addition, the core of the microparticles can contain a plasticizer.Exemplary plasticizers include, for example, Plasacryl® available fromIMTech, PA, USA, and triethyl citrate available from Morflex, N.C., USA.

In addition, the core of the microparticles optionally can contain acontrolled release agent that controls the release of thepharmaceutically active agent. Exemplary controlled release agents canbe selected from the group consisting of starch, starch derivatives,cellulose derivatives, xanthan gum, polyethylene glycol, polyvinylacetate, polyvinyl alcohol, and mixtures thereof. In a preferredembodiment, the controlled release excipient includes a starchderivative that is a cross-linked high amylose starch, which providesthe controlled release of the pharmaceutically active agent for at least12 hours, for at least 18 hours, or for at least 24 hours. Thecross-linked high amylose starch can be cross-linked with phosphorusoxychloride and/or can contain hydroxypropyl side chains. In certainembodiments, a suitable controlled release agent is commerciallyavailable from Labopharm, Inc., Laval, Canada, under the trademarkCONTRAMID®. The synthesis of the CONTRAMID® excipient is described inU.S. Pat. No. 6,607,748.

The core of the microparticles containing a pharmaceutically activeagent can be prepared by a variety of methods, including, for example,wet granulation and extrusion-spheronization. During wet granulation,microparticles are prepared using, for example, a fluid bed rotorgranulator. The wet granulation process comprises, for example, (i)wetting the powder to form wet granules; (ii) exposing the wet granulesto tumbling or spheronization, and (iii) drying the resulting product.Alternatively, the pellets can be produced by extrusion-spheronization,which has the advantage of being highly reproducible, easy to scale up,cost effective, and produces substantially perfect sphericalmicroparticles. Extrusion-spheronization comprises, for example, (i)wetting the powder blend with an aqueous or organic solution generallycontaining a binder to form a wet homogeneous mass suitable for wetextrusion, (ii) extruding the wet mass to form cylindrical extrudates ofuniform shape and size, and (iii) spheronizing the wet extrudates usinga spheronizer, where, for example, a fast spinning disc, breaks theextrudates into smaller microparticles and rounds them to form spheres.

The cores of the microparticles can be coated with a controlled-releasecoating that is sufficiently flexible to be deformed under compressionduring tablet formation without undergoing fracture. Suitable controlledrelease agents are described in the previous section. In one embodiment,the controlled release coating comprises polymethacrylate (e.g.,Eudragit® RS, available from Degussa/Evonik Industries, NJ, USA).Eudragit® RS30D grade, which is particularly useful, is an aqueousdispersion (30% w/w) of a polymeric mixture of ethyl acrylate, methylmethacrylate, and trimethylammonioethyl methacrylate at a ratio of1:2:0.1 (w/w). The Eudragit® RS grade is designed to formwater-insoluble film coats for sustained release formulations. TheEudragit® RS grade forms a highly flexible film coat with lowpermeability. Another useful coating material includes Eudagrit® RL30D55, available from Degussa/Evonik Industries, NJ, USA. Anothercontrolled release coating comprises ethyl cellulose sold under thetradename Surelease®. Another controlled release coating includesKollicoat® SR, available from BASF Fine Chemicals. In one approach, thecore of the microparticles is coated using a fluid bed coater equippedwith a bottom spray.

The resulting particles, depending upon their composition and method offabrication have an average diameter in the range of from about 1 μm toabout 1000 μm. In certain embodiments, the microparticles have anaverage diameter of from about of 200 μm to about 900 μm, or from about300 μm to about 800 μm. In certain embodiments, the resultingmicroparticles have an average diameter of about 700 μm. In certainother embodiments the microparticles have an average diameter of fromabout 1 μm to about 400 μm, from about 5 μm to about 300 μm, or fromabout 10 μm to about 200 μm. In certain embodiments, the resultingmicroparticles have an average diameter of about 100 μm.

D. Pharmaceutically Active Agents

It is understood that the compositions described herein can be used forthe delivery of one or more pharmaceutically active agents. In certainembodiments, the controlled release microparticles can contain one ormore pharmaceutically active agents. In addition, it is understood thatthe compositions of the invention can contain a number of differentmicroparticles, with one population of microparticles containing onepharmaceutically active agent and another population of microparticlescontaining a second, different pharmaceutically active agent.Furthermore, it is understood that one or more of the pharmaceuticallyactive agents can be present in microparticles whereas one or more otherpharmaceutically active agents can be present in a free form within thecomposition (i.e., not disposed in or associated with a microparticle).

Many pharmaceutically active agents can benefit from being deliveredusing the formulations described herein. The Controlled Substances Act(CSA), Title II of the Comprehensive Drug Abuse Prevention and ControlAct of 1970, places all substances that are regulated under existingFederal Law into one of five schedules based upon the substance'smedicinal value, harmfulness, and potential for abuse or addiction. Theformulations of the invention are preferably used to deliver those drugsclassified as Schedule II, III, IV and V drugs. Similarly, although anydrug in which there is a benefit in having controlled release of thedrug can be incorporated into formulations of the invention, theformulations described herein are particularly useful in the deliveryof, for example, CNS and respiratory stimulant agents, analgesics (forexample, opioid analgesics), hypnotic agents, anxiolytic agents, andagents with a narrow therapeutic index. For purposes of this invention,pharmaceutically active agents are intended to encompass salts, esters,and the prodrugs of the pharmaceutically active agents.

Exemplary opioid analgesics include, for example, alfentanil,buprenorphine, butorphanol, carefentanil, codeine, dezocine,diacetylmorphine, dihydrocodeine, dihydromorphine, diprenorphine,etorphine, fentanyl, hydrocodone, hydromorphone,β-hydroxy-3-methylfentanyl, levo α-acetylmethadol, levorphanol,lofentanil, meperidine, methadone, morphine, nalbuphine, oxycodone,oxymorphone, pentazocine, pethidine, propoxyphene, remifentanil,sufentanil, tilidine, tramadol hydrochloride, or a mixture thereof

In certain embodiments containing an opioid analgesic, the solidcomposition can further include acetaminophen as a second, differentpharmaceutically active agent. Depending upon the desired properties ofthe composition, the acetaminophen can be included in the first layer,the second layer, or both the first and second layers. In certainformulations, the acetaminophen is not included within themicroparticles as it is believed that, for certain users, the rapidrelease of acetaminophen may serve as an additional deterrent tocrushing the compositions because acetaminophen is generally known tohave toxicity at high concentrations.

Exemplary hypnotics include, for example, benzodiazepines andnon-benzodiazepines. Exemplary benzodiazepines include, but are notlimited to, alprazolam, diazepam, flurazepam, loprazolam, mexazolam,nitrazepam, and the like. Exemplary non-benzodiazepines include, but arenot limited to, barbiturates (for example, butobarbitone,phenobarbitone, or amylobarbitone) chlormethiazole, eszopiclone,ramelteon, zaleplon, zopiclone, zolpidem, and the like.

Exemplary anxiolytic agents include, but are not limited to,amphetamine, buspirone, barbiturates, benzodiazepines (for example,alprazolan, bromazepam, brotizolam, camazepam, chlordiazepoxide,clobazam, clonazepam, desalkylflurazepam, diazepam, flunitrazepam,flurazepam, lorazepam, lometazepam, medazepam, metaclazepam, midazolam,nitrazepam, nordazepam, oxazepam, pentylenetetrazole, prazepam,temazepam, tetrazepam, and triazolam) and the like.

Exemplary CNS and respiratory stimulatory agents include, but are notlimited to xanthines (for example, caffeine and theophylline),amphetamines (for example, amphetamine, benzphetamine hydrochloride,dextroamphetamine, dextroamphetamine sulfate, levamphetamine,levamphetamine hydrochloride, methamphetamine, and methamphetaminehydrochloride), and miscellaneous stimulants such as methylphenidate,methylphenidate hydrochloride, modafinil, pemoline, sibutramine, andsibutramine hydrochloride.

Pharmaceutically active agents with a narrow therapeutic index include,for example, amiodarone, amphotericin, cabamazepine, clozapine, digoxin,disopyramide, lithium carbonate, minoxidil, phenytoin, primidone,procainamide, quinidine, theophylline, valproic acid, and warfarin.

It will be appreciated that the amount of the pharmaceutically activeagent present in the abuse-resistant formulation depends upon thetherapeutic dose required in conventional tablets. In generally, eachpharmaceutically active agent is present in an amount ranging from about0.5 mg to about 900 mg by weight, from about 1 mg to about 700 mg byweight, from about 1 mg to about 600 mg by weight, from about 1 mg toabout 500 mg, from about 1 mg to about 400 mg, from about 1 mg to about300 mg, from about 1 mg to about 200 mg, and from about 10 mg to about200 mg. It is understood, however, that the actual dosage will dependupon the particular pharmaceutically active ingredient and its proposeduse.

It is understood that the intact compositions described herein can beproduced using techniques known to those in the formulary arts. Anexemplary protocol for producing controlled release tablets is describedin Example 1. It is understood, however, that other approaches can beused to make formulations of the invention.

In certain embodiment, the formulations have a hardness in the range offrom about 100 N to about 500 N, or from about 150 N to about 400N, orfrom about 200 N to about 400N, or from about 300 N to about 400 N. Incertain embodiments, the formulations have a hardness from about 130 Nto about 280 N, from about 130 N to about 210 N, from about 130 N toabout 195 N, from about 150 N to about 250 N, from about 150 N to about200 N, from about 150 N to about 180 N, from about 160N to about 195 N,from about 160 N to about 180 N, from about 180 N to about 230 N, fromabout 200 N to about 250 N, from about 200 N to about 260 N, from about205 N to about 280 N, from about 210 to about 250 N, or from about 210 Nto about 230 N.

In certain embodiments, for example, an oral dosage form containingoxycodone and acetaminophen can have a hardness within one or more ofthe ranges set forth above.

The composition, when made, can be used to administer a pharmaceuticallyactive agent to a mammal, for example, a human, in need of thepharmaceutically active agent (for example, an opioid analgesic for painmanagement). It is understood that the exact dosage will vary dependingon the symptoms, age, body weight, severity of the disease to be treatedand can be optimized through routine experimentation known to those ofskill in the art.

EXAMPLES

Practice of the invention will be more fully understood from theforegoing examples, which are presented herein for illustrative purposesonly, and should not be construed as limiting the invention in any way.

Example 1 Exemplary Oxycodone HCl/Acetaminophen Tablet

This Example describes an exemplary misuse preventative tablet and howit can be made. The composition comprises a mixture of acetaminophen(650 mg) and oxycodone HCl (25 mg). Oxycodone is a drug used for thetreatment of moderate to moderately severe pain, which is capable ofbeing abused and for which over exposure via misuse can lead to harmfulside effects. The tablet has a bilayer core with a non-functional(aesthetic) coating. In this Example, the superabsorbent material isdisposed within the controlled release layer. The formulation of thetablet is set forth in Table 1, and the manufacture of each of thecomponents for the formulation appear in the following sections of thisExample.

TABLE 1 Tablet Composition Ingredients (Mg) (%) First layer (controlledrelease) Oxycodone (as oxycodone microparticles) 173.79 24.72 COMPAP ®(which includes acetaminophen) 433.33 61.64 Carbopol 71 G 42.02 5.98Xanthan gum 80 mesh 42.02 5.98 Colloidal silicon dioxide (Cab O sil)2.95 0.42 Sodium stearyl fumarate (Pruv) 8.86 1.26 Total 703.00 100.00Second layer (rapid release) COMPAP ® (which includes acetaminophen)288.89 89.72 Microcrystalline Cellulose PH102 19.77 6.14 Croscaramellosesodium AcDiSol 6.70 2.08 Colloidal silicon dioxide (Cab O sil) 1.68 0.52Sodium stearyl fumarate (Pruv) 4.83 1.50 FD&C Yellow #6 0.13 0.04 Total322.00 100.00

Throughout the examples, COMPAP® (Mallinckrodt, Inc.) is a compressiblecomposition that comprises an admixture of acetaminophen andpre-gelatinized starch, where the percentage of acetaminophen in thecomposition can vary slightly depending upon the batch of COMPAP®. Tocompensate for this variability, the amount of COMPAP® is varied in theblend of excipients to be compressed. Corresponding changes are made tothe amount of microcrystaline cellulose in order to maintain tabletweight. In addition, the amount of oxycodone or other active ingredientcontained within the microparticles can vary, so the amount ofmicroparticles may be adjusted to keep the drug content constant.

A. Manufacture of Oxycodone Microparticles

The microparticles were produced by mixing the components set forth inTable 2 (except for the Eudragit NE 30D and Talc). The resulting mixturewas subjected to extrusion and spheronization, and the resultingmicroparticles were coated with the Eudragit NE 30D and talc in a fluidbed coater equipped with a bottom spray. The core of the tablet was abilayer. The oxycodone containing microparticles were incorporated inthe slow release layer of the bilayer whereas the acetaminophen, asCOMPAP® which was in free form and not incorporated into microparticles,was present in both the rapid release layer and the slow release layer.

TABLE 2 Ingredients Mg/tablet % Composition Oxycodone HCl 20.0 11.51Cellulose microcrystalline (Avicel PH101) 37.3 21.49 Contramid ®excipient 2.7 1.53 Lactose monohydrate 73.4 42.22 Eudragit NE 30D 20.011.51 Talc 20.0 11.51 Colloidal silicon dioxide 0.4 0.23 Total 173.8100.00

B. Manufacture of the Bilayer

The composition of the first layer (controlled release layer) containingCOMPAP® and the oxycodone containing microparticles, and the compositionof the second layer containing COMPAP® (which includes acetaminophen)are shown in Table 1. The bilayer was prepared by mixing the componentsof each layer and then compressing the materials in a tablet press toform a tablet having a hardness of about 210 N.

C. Aesthetic Coat

The bilayer tablet was coated with an aesthetic coat using the Opaglosingredients set forth in Table 3 using a pan coating machine to form thefinal coated tablet.

TABLE 3 Ingredients Mg/tablet % tablet Opaglos II Gray 30.75 3.0 OpaglosII Clear 10.25 1.0

The in vitro release properties of the resulting tablets were measuredin a U.S.P. Type III Apparatus in potassium phosphate buffer at pH 6.8for 12 hours, 0.1 M hydrochloric acid at pH 1.2 for 12 hours, 0.1 Mhydrochloric acid at pH 1.2 for 1 hour followed by potassium phosphatebuffer at pH 6.8 for 11 hours, and in 40% ethanol. As shown in FIG. 3A,the release profiles for oxycodone were substantially the same acrossthe pH range tested. In addition, as shown in FIG. 3B, the releaseproperties for acetaminophen were substantially the same across the pHrange tested.

The in vitro release properties of three lots of tablets were measuredin a U.S.P. Type I Apparatus in potassium phosphate buffer at pH 6.8.The effect of halving or quartering the tablets on the release ofoxycodone is shown in FIG. 4A (half tablet) and 4B (quarter tablet). Theeffect of halving or quartering the tablets on the release ofacetaminophen is shown in FIG. 5A (half tablet) and 5B (quarter tablet).The partial tablets maintained a controlled release for 12 hours, withno evidence of dose dumping.

Crushed tablets were prepared using a conventional pill crusher. The invitro release properties of the crushed tablets were measured in aU.S.P. Type I Apparatus under a variety of conditions. FIG. 6Aillustrates the release kinetics of oxycodone in basified potassiumphosphate aqueous solution at pH 10.0, potassium phosphate buffer at pH6.8 and acidified potassium phosphate aqueous solution at pH 3.0, water,water containing 20% ethanol and water containing 40% ethanol.Controlled release of oxycodone was maintained under all conditions withno evidence of dose dumping. FIG. 6B illustrates the release kinetics ofacetaminophen, which is less controlled than that of oxycodone. Theincreased release allows for deterrence of injecting or snorting thecrushed powder, which is potentially hepatotoxic. Complete sequestrationof acetaminophen after crushing would not allow for such deterrence.

When exposed to water, a crushed tablet rapidly formed a gel, forexample, within 21 seconds. Crushed tablets were exposed to the 10 mL ofthe liquids shown in Table 4. The resulting mixtures were agitated in amechanical shaker for 120 minutes, then allowed to stand for 15 minutesto determine whether any separation of gel and liquid occurred.

TABLE 4 Oxycodone Acetaminophen Liquid % released* % released* Tap WaterThick gel Thick gel Ethanol (40% (v/v)) Thick gel Thick gel Acidic Media(pH 3.0) Thick gel Thick gel Basic Media (pH 10.0) Thick gel Thick gelAs illustrated in Table 4, a thick gel formed when the aqueous solventcontained 40% ethanol or had a pH in the range from 3 to 10. Because thegel did not separate into a solid and supernatant, no liquid wasavailable for analysis to determine the amount of oxycodone oracetaminophen that may have eluted from the composition.*

In order to simulate the effect of intravenous or nasal administrationof a crushed tablet, a tablet was crushed and mixed with 2 mL of tapwater or water containing 40% ethanol as shown in Table 5. A hard gelformed in both cases. To extract liquid from the hard gel for analysis,a cotton wool filter was placed on the tip of a syringe and a smallamount of liquid was extracted under heavy suction. The extracts wereanalyzed for oxycodone and acetaminophen content.

TABLE 5 Extract Liquid % Oxycodone % Acetaminophen Water 0.0 0.14Ethanol (40% v/v) 0.0 0.12

The results show that no oxycodone was detected in the extracts, while anegligible amount of acetaminophen was present in both water and 40%ethanol.

To determine the amount of active ingredient release upon geldisruption, crushed tablets were added to either 100 mL of water,acidified potassium phosphate aqueous solution buffer pH 3.0, or watercontaining 40% ethanol. The resulting gels were disrupted by vigorousstirring for 1 minute. The mixtures were assayed for oxycodone andacetaminophen content at 15, 30, and 60 seconds as shown in Table 6.

TABLE 6 % Oxycodone content % Acetaminophen content 15 30 60 15 30 60Extract Liquid sec sec sec sec sec sec Water 0.8 1.7 2.1 30.9 42.1 49.2Ethanol (40% v/v) 2.0 2.7 4.1 29.9 44.1 52.4 Acidic Media 2.0 3.5 5.348.2 52.1 68.4 (pH 3.0)

The results show a rapid release of acetaminophen, which could deterpotential intravenous or nasal administration because high doses ofacetaminophen are known to be hepatotoxic. Unlike acetaminophen,oxycodone is present as microparticles in the tablet formulation suchthat release of oxycodone following crushing was minimal.

Example 2 Exemplary Oxycodone HCl/Acetaminophen Tablet

This Example describes the manufacture and testing of a twice-a-daytablet containing oxycodone HCl (20 mg) and acetaminophen (650 mg). Thebilayer tablet contains microparticles containing oxycodone HCl andContramid®, and coated with an enteric coating. The resulting bilayer,however, was encapsulated with a non functional (aesthetic) coat. Thesuperabsorbent material was disposed in the slow release layer.

The formulation of the tablet is set forth in Table 7, and themanufacture of each of the components for the formulation appear in thefollowing sections of this Example.

TABLE 7 Tablet Composition Ingredients (Mg) (%) First Layer (SlowRelease) Oxycodone microparticles (coated at 198.4 26.40 10% EudragitNE + 15% enteric coating) COMPAP ® (which includes acetaminophen) 469.4462.46 Carbopol 71 G 36 4.79 Xanthan gum 80 mesh 36 4.79 Colloidalsilicon dioxide (Cab O sil) 2.97 0.40 Sodium stearyl fumarate (Pruv)8.83 1.17 Total 751.64 100 Second layer (Fast Release) COMPAP ® (whichincludes acetaminophen) 252.77 88.42 Microcrystalline Cellulose PH10219.76 6.91 Croscaramellose sodium AcDiSol 6.7 2.34 Colloidal silicondioxide (Cab O sil) 1.68 0.59 Sodium stearyl fumarate (Pruv) 4.83 1.69FD&C Yellow #6 0.13 0.05 Total 285.87 100

A. Manufacture of Oxycodone Microparticles

The microparticles were produced by mixing the first four components setforth in Table 8. The resulting mixture was subjected to extrusion andspheronization, and the resulting microparticles were coated with theremaining four excipients (Eudragit NE30D, talc, Eudragit L30D-55,triethyl citrate) in a fluid bed coater equipped with a bottom spray.Microparticles coated with a Eudragit L30D-55 coat withstand dissolutionat low pH, such as pH 1-3, and prevent the release of oxycodone. Thecoating dissolves at higher pH, but its mechanical removal is minimalwhen the tablet is crushed. The coating prevents the release ofoxycodone at low pH in both intact and crushed tablets.

The core of the tablet was a bilayer. The oxycodone containingmicroparticles were incorporated in the slow release layer of thebilayer whereas the acetaminophen, as COMPAP® which was in free form andnot incorporated into microparticles, was present in both the rapidrelease layer and the slow release layer.

TABLE 8 Ingredients Mg/tablet % Composition Oxycodone HCl 20.0 10.08Cellulose microcrystalline (Avicel PH101) 37.3 18.82 Contramid ® 2.71.34 Lactose monohydrate 73.3 36.96 Eudragit NE30D 13.3 6.72 Talc 25.312.77 Eudragit L30D-55 24.0 12.1 Triethyl citrate 2.4 1.21 Total 198.4100.00

B. Manufacture of Bilayer

The composition of the first layer (controlled release layer) containingCOMPAP® and the oxycodone containing microparticles, and the compositionof the second layer containing acetaminophen are shown in Table 7. Thebilayer was prepared by mixing the components of each layer and thencompressing the materials in a tablet press to form a tablet having ahardness of about 230 N.

C. Aesthetic Coating

The resulting bilayer then was coated with the Opaglos ingredients setforth in Table 9 by using a pan coating machine to form the final coatedtablet.

TABLE 9 Ingredients Mg/tablet % tablet Opaglos II Green 31.12 3.0Opaglos II Clear 10.38 1.0

The in vitro release properties of the resulting tablets were measuredin a U.S.P. Type I Apparatus in acid pH 1.2 for 12 hours, phosphatebuffer pH 6.8 for 12 hours, and acid pH 1.2 for 1 hour, followed byphosphate buffer pH 6.8 for 11 hours. The release kinetics were measuredon intact tablets. As shown in FIG. 7A, the release profiles foroxycodone demonstrate the delay in release for at least 1 hour at lowpH. As shown in FIG. 7B, a rapid release of acetaminophen was observed.Release kinetics similar to Example 1 were observed for half and quartertablets (data not shown).

The in vitro release properties of the resulting tablets were measuredin a U.S.P. Type I Apparatus in acid pH 1.2 for 1 hour and phosphatebuffer pH 6.8 for 1 hour for crushed tablets. As shown in FIG. 8A, therelease profiles for oxycodone demonstrate the delay in release for atleast 1 hour at low pH. As shown in FIG. 8B, a more rapid release ofacetaminophen was observed.

Example 3 Exemplary Oxycodone HCl/Acetaminophen Tablet

This Example describes the manufacture and testing of a tablet (BID)containing oxycodone HCl (20 mg) and acetaminophen (650 mg). The tabletcomprises a bilayer core surrounded by an enteric, controlled releasecoating (namely, Eudragit L30D55). The microparticles, however, did nothave a controlled release coating. The superabsorbent material isdisposed in the slow release layer.

The microparticles were produced by mixing the components set forth inTable 10 (except for the Eudragit NE 30D and Talc). The resultingmixture was subjected to extrusion and spheronization, and the resultingmicroparticles were coated with the Eudragit NE 30D and talc in a fluidbed coater equipped with a bottom spray.

TABLE 10 Ingredients Mg/tablet % Composition Oxycodone HCl 20.0 11.51Cellulose microcrystalline (Avicel PH101) 37.3 21.49 Contramid ® 2.71.53 Lactose monohydrate 73.4 42.22 Eudragit NE 30D 20.0 11.51 Talc 20.011.51 SiO₂ 0.4 0.23 Total 173.8 100.00

The composition of the core, which was a bilayer, is set forth in Table11. The oxycodone containing microparticles were incorporated in theslow release layer of the bilayer whereas the acetaminophen, as COMPAP®which was in free form and not incorporated into microparticles, waspresent in both the rapid release layer and the slow release layer.

TABLE 11 Tablet Composition Ingredients (Mg) (%) First layer (slowrelease) Oxycodone (provided as oxycodone microparticles) 173.79 24.72COMPAP ® (which includes acetaminophen) 433.33 61.64 Carbopol 71 G 42.025.98 Xanthan gum 80 mesh 42.02 5.98 Colloidal silicon dioxide (Cab Osil) 2.95 0.42 Sodium stearyl fumarate (Pruv) 8.86 1.26 Total 703.00100.00 Second layer (rapid release) COMPAP ® (which includesacetaminophen) 288.89 89.72 Microcrystalline Cellulose PH102 19.77 6.14Croscaramellose sodium AcDiSol 6.70 2.08 Colloidal silicon dioxide (CabO sil) 1.68 0.52 Sodium stearyl fumarate (Pruv) 4.83 1.50 FD&C Yellow #60.13 0.04 Total 322.00 100.00

The bilayer core was prepared by mixing the components of each layer andthen compressing the materials in a tablet press. The bilayer tabletshad a hardness in the range of 190 to 230 Newtons. The resulting bilayercore was then coated with Eudragit L30D 55 by using a pan coatingmachine. The resulting coating contained 82 mg of Eudragit L30D 55,which accounted for 8% of the weight of the tablet.

The in vitro release kinetics of the resulting tablet were measured in aU.S.P. Type III Apparatus at 20 dpm after incubation in 0.1 Mhydrochloric acid at pH 1.2 for 1 hour followed by incubation inphosphate buffer pH 6.8 for 11 hours. The results shown in FIG. 9indicate that no oxycodone was released from the tablet when incubatedin 0.1 M hydrochloric acid, but the oxycodone was released in acontrolled manner when the buffer was changed to phosphate buffer pH 6.8after 1 hour.

Example 4 Exemplary Oxycodone HCl/Acetaminophen Tablet

This Example describes the manufacture and testing of a tablet (BID)containing oxycodone HCl (20 mg) and acetaminophen (650 mg). The tabletcomprises a bilayer core, where the superabsorbent material (Carbopol71G) and lipids (Compritol 888 ATO) are present in the controlledrelease layer. The lipids are designed to swell at low pH therebyminimizing release of oxycodone HCl. The composition of the bilayer coreis set forth in Table 12, and the manufacture of each of the componentsfor the formulation appear in the following sections of this Example.

TABLE 12 Tablet Composition Ingredients (Mg) (%) Rapid Release LayerCOMPAP ® (which includes acetaminophen) 288.90 89.72 MicrocrystallineCellulose PH102 19.76 6.14 Croscaramellose sodium AcDiSol 6.70 2.08Colloidal silicon dioxide (Cab O sil) 1.68 0.52 Sodium stearyl fumarate(Pruv) 4.83 1.50 FD&C Yellow #6 0.13 0.04 Total 322.00 100.00 SlowRelease Layer Oxycodone microparticles 148.58 17.38 COMPAP ® (whichincludes acetaminophen) 433.42 50.70 Carbopol 71 G 90.00 10.53 Compritol888 ATO 171.00 20.00 Colloidal silicon dioxide (Cab O sil) 2.96 0.35Sodium stearyl fumarate (Pruv) 8.83 1.03 Total 854.79 100.00

A. Manufacture of Oxycodone Microparticles

The microparticles were produced by mixing the components set forth inTable 13 (except for the Eudragit NE 30D and Talc). The resultingmixture was subjected to extrusion and spheronization, and the resultingmicroparticles were coated with the Eudragit NE 30D and talc in a fluidbed coater equipped with a bottom spray.

TABLE 13 Ingredients Mg/batch % Composition Oxycodone HCl 124.8 12.48Cellulose microcrystalline (Avicel PH101) 232.9 23.29 Contramid ®excipient 16.6 1.66 Lactose monohydrate 457.4 45.74 Eudragit NE 30D 83.28.32 Talc 83.2 8.32 SiO₂ 2.0 0.20 Total 1000 100.00

B. Manufacture of Bilayer

The core of the tablet was a bilayer. The oxycodone containingmicroparticles were incorporated in the slow release layer of thebilayer whereas the acetaminophen, as COMPAP®, which was in free formand not incorporated into microparticles, was present in both the rapidrelease layer and the slow release layer.

The composition of the first layer (controlled release layer) containingCOMPAP® (containing acetaminophen) and the oxycodone containingmicroparticles, and the composition of the second layer containingCOMPAP® are shown in Table 12. The bilayer was prepared by mixing thecomponents of each layer and then compressing the materials in a tabletpress (Manesty, UK) to form a tablet having a hardness of about 150 N.

C. Aesthetic Coating

The resulting bilayer was coated with an aesthetic coating using theOpaglos ingredients set forth in Table 14 by using a pan coating machineto provide the final coated tablet.

TABLE 14 Ingredients Mg/tablet % Composition Opaglos II Gray 30.75 3.0Opaglos II Clear 10.25 1.0

The in vitro release properties of the resulting tablets were measuredin a U.S.P. Type III Apparatus in phosphate buffer pH 6.8. The releasekinetics were measured on intact tablets. As shown in FIG. 10A, therelease profile of oxycodone in tablets comprising Compritol in thecontrolled release layer was comparable to tablets having an entericcoat on the oxycodone microparticles, such as the data at pH 6.8 forintact tablets in Example 2 under similar conditions (FIG. 7A).Likewise, the release kinetics for acetaminophen shown in FIG. 10B weresimilar to that of Example 2 (FIG. 7B).

The in vitro release properties of the resulting tablets, when crushed,were measured in a U.S.P. Type I Apparatus in acid at pH 1.2. As shownin FIG. 11A, the release profile of oxycodone in tablets comprisingCompritol showed a greater release of oxycodone than the crushed tabletsof the Example 2 formulation (FIG. 8A) under the same conditions.However, no dose dumping of oxycodone was observed. In comparison toExample 2 for acetaminophen release from crushed tablets (FIG. 8B),acetaminophen was not released as fast from the Compritol containingcrushed tablets (FIG. 11B).

Example 5 Exemplary Controlled Release Methylphenidate Formulation

This Example describes the manufacture and testing of a tabletcontaining methylphenidate in a 12 hour controlled release bilayerformulation. While the tablet is uncoated, an aesthetic or functional(such as enteric) coat can be applied. The superabsorbent material isdisposed within the slow release layer. The formulation of the tablet isset forth in Table 15, and the manufacture of each of the components forthe formulation appear in the following sections of this Example.

TABLE 15 Lot 1 Lot 2 Lot 3 Lot 4 Ingredients % Mg/tab % Mg/tab % Mg/tab% Mg/tab Fast release layer compositions Film coated methylphenidate27.31 27.31 27.31 27.31 27.31 27.31 27.31 27.31 microparticles Avicel PH102 69.17 69.17 69.17 69.17 69.17 69.17 69.17 69.17 Croscarmellose(Ac-Di-Sol) 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 Colloidal silicondioxide 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Sodium stearyl fumarate 1.001.00 1.00 1.00 1.00 1.00 1.00 1.00 Total Core 100.0 100.0 100.0 100.0100.0 100.0 100.0 100.0 Slow release layer compositions Film coatedmethylphenidate 44.22 154.8 44.22 154.8 44.22 154.8 44.22 154.8microparticles Avicel PH 102 — — — — — — — — Carbopol 71G 13.57 47.513.57 47.5 13.57 47.5 20.35 71.24 Xanthan gum 13.57 47.5 0 0 0 0 0 0Kollidon SR 13.57 47.5 13.57 47.5 20.35 71.24 20.35 71.24 Plasdone S-63013.57 47.5 27.14 95.0 20.35 71.24 13.57 47.5 Colloidal silicon dioxide0.50 1.8 0.50 1.8 0.50 1.8 0.50 1.8 Sodium stearyl fumarate 1.00 3.51.00 3.5 1.00 3.5 1.00 3.5 Total coat 100.0 350.0 100.0 350.0 100.0350.0 100.0 350.0 Total tablet weight 450.0 450.0 450.0 450.0

A. Manufacture of Methylphenidate Microparticles

Microparticles of methylphenidate having the composition set forth inTable 16 were formulated using an extrusion microspheronization process.

TABLE 16 Ingredients % Composition Methylphenidate hydrochloride 29.66MCC Avicel PH 101 55.09 Eudragit RS30D ® + Plasacryl ® + Triethylcitrate 15.25 Total 100.00

The methylphenidate hydrochloride and MCC Avicel PH 101 were mixed in amixer for 3 minutes under low shear conditions. The dry blend then waswetted under agitation in the same mixer by gradually adding water untila homogeneous wet mass suitable for extrusion was produced. The wet massthen was extruded at a constant speed (45 rpm) using a LaboratoryMultigranulator extruder model MG-55 from LCI, Inc., NC, USA equippedwith a dome die having a 0.6 mm diameter hole and a fixed extrusion gap.The extrudates then were spheronized at a constant speed (1800 rpm)using a Marumerzier Model QJ-230T from LCI, Inc., NC, USA. The wetmicroparticles were dried at 45° C. in a fluid bed (Glatt, GPGC-1) untila moisture content of about 2% was achieved. The resultingmicroparticles then were coated via fluidized bed coating using acoating solution containing Eudragit RS30D®, a film that resistscrushing, but is not an enteric coating.

B. Manufacture of the Bilayer

The composition of the first layer (fast release layer) containing themethylphenidate microparticles (fast release) and the second layer (slowrelease layer) containing the methylphenidate microparticles (controlledrelease) are shown in Table 15. The bilayer was prepared by mixing thecomponents of each layer and then compressing the materials using atablet press to form a tablet having a hardness of about 250 N.

Four lots of tablets were assayed for their in vitro release propertiesof methylphenidate in a U.S.P. Type II Apparatus in acidified water, pH3.5. The release kinetics were measured on intact tablets. As shown inFIG. 12, no dose dumping was observed. Approximately 15% methylphenidatewas released during the first hour followed by a quasi-zero orderrelease kinetics of methylphenidate up to 12 hours.

Example 6 Exemplary Oxycodone HCl/Acetaminophen Tablets

This Example illustrates the preparation of a bilayer tablet containingoxycodone HCl (20 mg) and acetaminophen (650 mg). One layer is a rapidrelease layer which contains acetaminophen, and the other layer is aslow release layer which includes oxycodone HCl microparticles andacetaminophen. In this Example, the superabsorbent material is disposedwithin the rapid release layer.

The formulation of the complete tablet is set forth in Table 17.

TABLE 17 Ingredients Mg/Tablet %/Tablet Oxycodone HCl (as Oxycodone HClmicro- 20.0 1.76 particles - theoretical content = 9.29%) COMPAP ®(which includes acetaminophen) 722.22 63.69 Microcrystalline cellulosePH101 37.32 3.29 Contramid ® bulk powder 2.67 0.24 Lactose monohydrate(Spray Dry) # 315 73.31 6.46 Eudragit NE30D 19.99 1.76 Talc Suprafino H32.99 2.91 Eudragit L30D-55 25.99 2.29 Triethyl citrate 2.60 0.23Mannitol 34.79 3.07 Microcrystalline Cellulose PH102 21.80 1.92Croscarmellose sodium AcDiSol 6.70 0.59 Carbomer homopolymer Type Acarbomer 941 34.79 3.07 (granular) FD&C Yellow #6 Aluminium Lake (35-42)0.13 0.01 Xanthan gum 80 mesh 80.00 7.05 Colloidal Silicon Dioxide 5.080.45 Sodium stearyl fumarate 13.66 1.20 Total 1134.03 100%

A. Manufacture of the Rapid Release Layer

COMPAP® and the ingredients of the rapid release layer given in Table 18were blended in a V-blender and set aside for a later stage of thetablet preparation.

TABLE 18 Tablet Composition Ingredients (Mg) (%) COMPAP ® (whichincludes acetaminophen) 252.78 75.30 Mannitol 34.79 10.36 Carbopol 71 G34.79 10.36 Croscarmellose sodium AcDiSol 6.70 2.00 Colloidal silicondioxide (Cab O sil) 1.68 0.5 Sodium stearyl fumarate (Pruv) 4.83 1.44FD&C Yellow #6 Aluminum Lake (35-42) 0.13 0.04 Total 335.70 100.00

B. Manufacture of Oxycodone HCl Microparticles

A wet mass of the first four ingredients (including oxycodone HCl) givenin Table 19 was extruded, spheronized, dried, and sieved to giveuncoated microparticles. The microparticles then were coated with apolymer solution of Eudragit NE30D and talc, followed by coating with apolymer solution of Eudragit L30D-55, triethyl citrate, and talc. Thecoated microparticles were then mixed with colloidal silicon dioxide andcured in an oven for 18 hours at 40° C.

TABLE 19 Microsphere Composition Ingredients (%) Oxycodone HCl 9.29Cellulose microcrystalline (Avicel PH101) 17.34 Contramid ® 1.24 Lactosemonohydrate 34.05 Eudragit NE30D 9.29 Talc 15.32 Eudragit L30D-55 12.07Triethyl citrate 1.21 Colloidal silicon dioxide 0.20 Total 100%

C. Manufacture of the Slow Release Layer

The oxycodone HCl microparticles and the ingredients of the slow releaselayer given in Table 20 were blended in a V-blender.

TABLE 20 Tablet Composition Ingredients (Mg) (%) Oxycodone HClmicroparticles (9.29% theoretical) 215.29 26.97 COMPAP ® (which includesacetaminophen) 469.44 58.80 Xanthan gum 80 mesh 80.00 10.02Microcrystalline cellulose PH102 21.80 2.73 Colloidal silicon dioxide(Cab O sil) 2.97 0.37 Sodium stearyl fumarate (Pruv) 8.83 1.11 Total798.33 100.00

D. Manufacture of the Tablet

The blended rapid release layer and the blended slow release layer werecompressed on a rotary bilayer Picolla 11-station press to providecaplet shaped tablets. The characteristics of the tablets obtained aresummarized in Table 21.

TABLE 21 Tablet Characteristics Typical Value Weight (mg) 1134  ShapeCaplet Length × width × thickness (mm) 18.5 × 9.3 × 7.6 Hardness (N) 180

The in vitro release kinetics of the resulting uncoated tablet weremeasured in a U.S.P. Type III Apparatus at 20 dpm in 250 mL of phosphatebuffer, pH 6.8. The release kinetics were measured on three batches ofintact tablets for 12 hours. As shown in FIGS. 13A and 13B, the releaseprofiles for oxycodone HCl and acetaminophen, respectively, weresubstantially the same across the three samples.

The in vitro release kinetics of oxycodone HCl from uncoated crushedtablets were measured in a U.S.P. Type I Apparatus in potassiumphosphate aqueous solutions at pH 1.2, 6.8, and 10, in water, and in 40%ethanol as shown in FIG. 14A. Less than 10% of the oxycodone HCl wasreleased in the various media. The in vitro release kinetics ofacetaminophen from uncoated crushed tablets were measured in a U.S.P.Type I Apparatus, in potassium phosphate aqueous solutions at pH 1.2,6.8, and 10, in water, and in 40% ethanol as shown in FIG. 14B. Lessthan 50% of the acetaminophen was released in one hour in aqueoussolution at pH 1.2, and less than 20% of the acetaminophen was releasedat one hour in the other media.

The in vitro release kinetics of oxycodone HCl and acetaminophen fromwhole and bisected (half) tablets were measured in a U.S.P. Type IIIApparatus, 20 dpm, in 250 mL of potassium phosphate buffer, pH 6.8. Thein vitro release kinetics of oxycodone HCl and acetaminophen frombisected (half) tablets were also measured in a U.S.P. Type IIIApparatus in 40% ethanol. The effect of bisecting the tablets on therelease of oxycodone is shown in FIG. 15A, which depicts releaseprofiles for whole and half tablets. The effect of bisecting the tabletson the release of acetaminophen is shown in FIG. 15B, which depictsrelease profiles for whole and half tablets. The half tablet and thefull tablet in general displayed similar release characteristics. Therelease of oxycodone and acetaminophen was slower in 40% ethanol fromwhole tablets than from bisected tablets.

The misuse prevention properties of the crushed uncoated tablets weredetermined by simple extraction into tap water, 40% ethanol, andpotassium phosphate aqueous solutions at pH 1.2, 6.8, and 10. Theresults are given in Table 22. Oxycodone release was well controlled inall media, while an increase in acetaminophen release was observed atbuffer pH 1.2 and 6.8.

TABLE 22 oxycodone HCl Acetaminophen 15 30 60 15 30 60 sec sec sec secsec sec Tests (%) (%) (%) (%) (%) (%) Tap Water 0.4 0.7 0.8 22.1 33.124.4 Ethanol (40%) 1.6 1.6 1.7 17.6 15.5 13.3 Buffer pH 1.2 1.4 2.3 1.332.4 45.3 43.8 Buffer pH 6.8 2.2 6.2 2.1 33.3 48.4 40.8 Buffer pH 10.00.5 0.7 0.6 21.2 26.4 28.0

Example 7 Exemplary Oxycodone HCl/Acetaminophen Tablets

This Example illustrates the preparation of a bilayer tablet containingoxycodone HCl (20 mg) and acetaminophen (650 mg). One layer is a rapidrelease layer which contains acetaminophen, and the other layer is aslow release layer which contains oxycodone HCl microparticles andacetaminophen. The superabsorbent material is disposed within the slowrelease layer. The formulation of the tablet is set forth in Table 23.

TABLE 23 Tablet Composition Ingredients (Mg) (%) Second Layer (RapidRelease) COMPAP ® (which includes acetaminophen) 252.8 88.4Microcrystalline Cellulose PH 102 19.8 6.9 Sodium Croscarmellose 6.7 2.4Colloidal Silicon Dioxide 1.7 0.6 Sodium stearyl fumarate (Pruv ®) 4.81.7 FD&C Yellow #6 Aluminum Lake (35-42) 0.1 0.05 Total 285.9 100.0First Layer (Slow Release) Oxycodone microparticles 214.8 25.8 COMPAP ®(which includes acetaminophen) 469.4 56.4 Microcrystalline Cellulose PH102 20.0 2.4 Carbopol ® 71G 38.5 4.6 Kollidon SR 57.8 7.0 HPMC K100M19.3 2.3 Colloidal Silicon Dioxide 3.0 0.4 Sodium stearyl fumarate(Pruv ®) 8.8 1.1 Total 831.7 100.0

A. Manufacture of the Rapid Release Layer

COMPAP® and the ingredients of the rapid release layer given in Table 23were blended in a V-blender and set aside for a later stage of thetablet preparation.

B. Manufacture of the Slow Release Layer

Oxycodone HCl microparticles were prepared according to the procedure ofExample 6. The microparticles and the ingredients of the slow releaselayer given in Table 23 were blended in a V-blender.

C. Manufacture of the Tablet

The blended rapid release layer and the blended slow release layer werecompressed on a rotary bilayer Picolla 11-station press to providecaplet shaped tablets. The characteristics of the tablets obtained aresummarized in Table 24.

TABLE 24 Tablet Characteristics Typical Value Weight (mg)  1117.6 ShapeCaplet Length × width × thickness (mm) 18.5 × 9.3 × 7.2 Hardness (N) 250

The in vitro release kinetics of oxycodone HCl and acetaminophen for theresulting intact bilayer tablets were measured in a U.S.P. Type IIIApparatus for 1 hour in acid medium, pH 1.2, followed by 11 hours inphosphate buffer, pH 6.8. The results are summarized in FIG. 16, whichshow that drug release for acetaminophen is faster than the release ofoxycodone.

The in vitro release kinetics of oxycodone HCl and acetaminophen for theresulting crushed bilayer tablets were measured in a U.S.P. Type IApparatus in 900 mL of deionized water at 100 rpm for 60 hours. Theresults are summarized in FIG. 17, which show that the drug release foroxycodone is much slower than the release of acetaminophen.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent and scientific documentsreferred to herein is incorporated by reference for all purposes.

EQUIVALENTS

Although the present invention has been illustrated by means ofpreferred embodiments thereof, it is understood that the inventionintends to cover broad aspects thereof without departing from the spiritand scope of the invention as defined in the appended claims.

1. A solid, compressed controlled release composition for oraladministration of at least one pharmaceutically active agent,comprising: (a) a first layer comprising a first population ofcontrolled release microparticles having a pharmaceutically active agentdisposed therein; (b) a second layer comprising a pharmaceuticallyactive agent disposed therein, wherein the second layer is adjacent thefirst layer; (c) a superabsorbent material comprising a cross-linkedacrylic acid polymer characterized in that the cross-linked acrylic acidpolymer absorbs at least 15 times its own weight of water, wherein thesuperabsorbent material is disposed within the first layer, the secondlayer, or both the first layer and the second layer, wherein thesuperabsorbent material comprises from about 10% to about 50% w/w of atleast one layer containing the superabsorbent material; (d) a controlledrelease agent disposed within the first layer, the second layer, or boththe first layer and the second layer; and (e) the composition having ahardness from about 200 N to about 400 N, and wherein the composition,(i) when intact and exposed to an aqueous medium, the pharmaceuticallyactive agent disposed in the second layer is initially released at afaster rate than the pharmaceutically active agent disposed in the firstlayer, (ii) when crushed and exposed to 2 mL of water, thesuperabsorbent material absorbs all of the water and creates a hard gelthat traps the microparticles, whereupon the hard gel and themicroparticles provide controlled release of the pharmaceutically activeagent disposed within the microparticles, and (iii) when broken andexposed to 900 mL of water in a U.S.P. Type I Apparatus with stirring at100 rpm for 30 minutes at 37° C., less than about 50% by weight of thepharmaceutically active agent originally present in the formulationbefore it was broken is released into the water. 2-40. (canceled)